More on NMDARs

My posts are all over the place (just like my thoughts) so in the hope I can restore some order, here is a review of NMDA related posts.

The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia

While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl-d-aspartate receptor (NMDAR) function. By highlighting postmortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics.

Targeting NMDARs and interneurons as a potential therapeutic strategy

“While current pharmacologic management of schizophrenia is dependent on D2 blockers, the evolving understanding of NMDAR and GABA interactions in schizophrenia holds promise for future therapeutics. As subunit-specific positive and negative allosteric modulators become available, this approach will increasingly be guided by selective targeting of subpopulations of NMDARs in an approach consistent with their neurodevelopmental expression.

Several drugs acting at the glycine binding site of NMDARs have been tested with mixed results over the past 20 years (Tuominen et al., 2005). Increasing glycine via dietary supplementation (Rosse et al., 1989, Costa et al., 1990, Javitt et al., 1994 and Heresco-Levy et al., 1999) or by inhibiting glycine reuptake with the competitive inhibitors sarcosine (Tsai et al., 2004) or bitopertin (Umbricht et al., 2014) has been shown to ameliorate negative symptoms of schizophrenia, although results have been inconsistent (Buchanan et al., 2007 and Goff, 2014). Other trials have supported the efficacy of high dose d-serine (Tsai et al., 1998, Heresco-Levy et al., 2005 and Kantrowitz et al., 2010) and low dose d-cycloserine (Goff et al., 1999b) but again, negative results have also been reported (Goff et al., 2005, Buchanan et al., 2007 and Weiser et al., 2012). The difficulty in replicating early positive findings may reflect the larger problem of heterogeneity in schizophrenia and the unreliability of clinical trials in this population. In addition, clozapine and possibly other second generation antipsychotics may enhance glutamatergic transmission, thereby complicating pharmacologic add-on strategies (Goff et al., 1999a, Goff et al., 2002, Wittmann et al., 2005 and Fumagalli et al., 2008). Repeated dosing with glycine site agonists may produce tachyphylaxis via endocytosis of NMDARs (Nong et al., 2003 and Parnas et al., 2005) which has led to intermittent dosing strategies (Goff et al., 2008 and Cain et al., 2014).

Intracellular pathways downstream of NMDARs may also present targets for pharmacologic intervention, as exemplified by nitric oxide augmentation by nitroprusside infusion (Hallak et al., 2013).

Of note, clozapine reverses the loss of PV in interneurons produced by repeated administration of NMDAR antagonists in adult mice (Cochran et al., 2003) and differs from other antipsychotics in showing efficacy for the glycine site of the NMDAR (Schwieler et al., 2008).

Another promising new pharmacologic approach targets the Kv3.1 channel which is primarily localized on PV + interneurons (Yanagi et al., 2014).

It remains to be established whether newer strategies, such as interneuron precursor transplants (Gilani et al., 2014) and transcranial electrical stimulation (Filmer et al., 2014) will prove effective in correcting interneuron functional deficits.

Given the many genetic links between schizophrenia and NMDAR pathways, a personalized medicine approach may produce larger and more consistent therapeutic benefits which could fundamentally advance our understanding of the illness and expand our available therapeutic options.”

A recent study by found “for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.” [1]

A 2013 article reviews the following NMDAR-based therapeutics (direct and indirect) which have also been somewhat covered on this site:

Glycine transporter-1 (GlyT-1) inhibitors [sarcosine]
d-Serine and d-amino acid oxidase (DAAO) inhibitors [Treatment of negative symptoms]
AMPA receptor positive allosteric modulators (PAMs)
mGlu2/3 receptor agonists and mGlu2 PAMs

M1 receptor allosteric agonists and PAMs [Review]

The evidence for the use of adjunctive glutamate modulators in schizophrenia is reviewed here and in a meta-analysis here.

Also reviewed in the article are:

mGlu5 receptor PAMs

“Numerous mGlu5 PAMs have been reported to be efficacious in various preclinical antipsychotic and cognition models. However, despite the mounting evidence that mGlu5 PAMs show promise as potential novel antipsychotics, drug discovery efforts face various challenges. In addition to ‘flat’ SAR and challenging activity landscapes, multiple series have exhibited ‘molecular switches’, whereby minor structural changes dramatically alter the pharmacological profile of a series. ‘Molecular switches’ may also apply to metabolites generated, rendering the development of potential candidates considerably more difficult. In addition, despite the potential therapeutic advantages of allosteric modulation, mechanism-based neurotoxic effects were recently observed in rats orally dosed with mGlu5 PAMs. The study was conducted with a small set of four structurally similar modulators, and the effects observed include convulsion-like behaviors, abnormal mouth movements, decreased activity, and neuronal cell death; similar behaviors elicited by i.c.v. administration of (S)-3,5-DHPG. Additional studies are required to ascertain what factors contributed to these adverse effects and to ensure that other structural classes of mGlu5 PAM scaffolds do not share these liabilities. These questions will likely need to be addressed prior to clinical evaluation of mGlu5 PAMs.”

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including autism spectrum disorders, drug addiction, schizophrenia, and Fragile X syndrome. There is strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder [2]. mGluR5 PAMs may have therapeutic utility in targeting specific aspects of impulsivity and executive dysfunction [3], resilience to chronic stress [4, 5]  and in treating disorders of sociability [6, 7]. A mGluR5 potentiator induces a pro-vigilant profile that is distinct from that of amphetamine, caffeine and modafinil [8]. mGluR5 signalling is important for synapse formation, neuroplasticity and long term potentiation as well as neuroprotection and has been shown to have a regulatory role in neuroinflammation [9].  mGluR5 PAMs and NAMs differentially affect mPFC dendritic spine structural plasticity [10].

mGlu5-GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia has been investigated and may open up new avenues for therapeutics [11]:

“Both mGlu5 and GABAB receptor modulators [GABAB (GS39783 and CGP7930), mGlu5 (CDPPB)] effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783, induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches.”

GABAB agonism has been proposed to be a novel strategy for modifying the regulatory role of prefrontal and striatal glutamate on striatal dopamine levels [12]:

“There has been substantial progress in translating animal models to human research focusing on schizophrenia (Modinos et al., 2015). It was shown that hippocampal electrophysiological activity enhances phasic firing of midbrain dopamine neurons (Grace et al., 2007), indicating a potential excitatory effect of glutamatergic input on midbrain dopamine firing via the hippocampus. Such glutamatergic input was shown to act locally at striatal presynaptic dopamine terminals via ionotropic (e.g., NMDA) receptors to facilitate tonic and impulse-independent phasic dopamine release (Borland and Michael, 2004), but glutamate may also indirectly enhance striatal dopamine via reuptake inhibition (Whitton, 1997). Regarding prefrontal glutamate, there is support that glutamatergic projections from the PFC influence dopaminergic projections to the striatum via GABA interneurons (Mora et al., 2002). Interestingly, infusion of the GABA(B) receptor agonists C4H12NO2P and baclofen into the PFC and striatum reduced dopamine levels, and this effect was reversed by a GABA antagonist (Balla et al., 2009). However, more research regarding specific receptor interactions potentially mediating the presented findings is needed.”

To conclude “mGlu5 receptor PAMs are effective in several animal models predictive of antipsychotic activity, and are currently tested in phase2 clinical trials” [13]

Kynurenine aminotransferase II (KATII) inhibitors

“Kynurenine aminotransferase II (KAT II) is involved in the KYNA biosynthetic pathway, and it is speculated that inhibition of KAT II would lower endogenous central KYNA levels and enhance NMDA receptor function. In fact, KAT II knockout mice showed reduced hippocampal KYNA levels (up to 70% reduction) and enhanced performance in cognition models relative to wild-type controls. The early KAT II inhibitor tool compounds (S)-ESBA and BFF-122 were poorly CNS penetrant and required central administration to assess antipsychotic activity.  However, recent KAT II inhibitors with improved oral bioavailability and CNS penetration are in various stages of pre-clinical development.  Pfizer’s pre-clinical candidate PF-04859989 was reported to produce a dose-dependent reduction in brain KYNA levels in rats (up to 80% reduction in the prefrontal cortex), and it demonstrated in vivo efficacy in rodent and nonhuman primate cognition models. The inhibitor also rapidly reversed anhedonia in a rodent chronic mild stress model, suggesting it may also improve negative symptoms.”

GluN2 subtype selective NMDA receptor modulators

“…the NMDA receptor is a heterotetrameric complex composed of two GluN1 and two GluN2 (GluN2A–D) sub-units. NMDA receptors may be comprised of the same or two different GluN2 sub-units, and the GluN2 sub-unit composition influences the expression and biophysical characteristics (e.g., open probability and channel gating kinetics) of the receptor. The GluN2A/B sub-units are found extensively throughout the forebrain, whereas GluN2C/D subunits are largely expressed in the cerebellum, basal ganglia, and on hippocampal and cortical interneurons.

Sub-unit selective GluN2B negative allosteric modulators (NAMs), such as ifenprodil, have been studied to assess therapeutic potential for various CNS disorders (e.g., depression, neuropathic pain, cerebral ischemia, Alzheimer’s disease, and Parkinson’s disease) and they have been used extensively as pharmacological tools to elucidate the role GluN2B NMDA receptors play in synaptic plasticity and cognition. Mutagenesis, molecular modeling, and X-ray crystallographic studies have shown that ifenprodil and similar analogues bind to a distinct allosteric site located on the GluN2B ATD.The GluN2B NAM traxoprodil (CP-101,606)  was reported to induce a dose-dependent impairment of cognitive function and memory as well as cause psychomimetic effects in Phase II clinical trials for traumatic brain injury and major depressive disorder.These data lend further support to the glutamate hypothesis and suggest subtype selective GluN2B PAMs may offer an approach to treat schizophrenia.

Despite considerable efforts in the area of GluN2B NAMs, drug-like and selective GluN2B PAMs have yet to be reported. The endogenous polyamine spermine was found to potentiate NMDA receptor-mediated responses at GluN2B by increasing glycine affinity and reducing proton-induced inhibition of the receptor. However, the compound is weakly potent (163 μM) and does not possess drug-like characteristics for further development. The neurosteroid pregnenolone sulfate (PS) was also found to potentiate GluN2B NMDA receptors, but it does not exhibit GluN2 subtype selectivity.

With the exception of GluN2B NAMs, GluN2 subtype selective modulation is a relatively nascent field. Selective modulation of NMDA receptor subtypes holds considerable promise for the treatment of various CNS disorders, including schizophrenia, and a better understanding of the distinct pharmacological roles of the GluN2 subtypes is to be gained as additional tool compounds exhibiting good selectivity and improved drug-like characteristics are identified.”

An approach not mentioned in the article is α5 GABAA receptor modulation. Recently it was found that negative modulation of α5 GABAA receptors may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion [14]:

“Reportedly, negative modulation of α5 GABAA receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of α5 GABAA receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-d-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of α5 GABAA receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia.”

See also:

Novel Treatments of Psychosis (2015)

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials. (2015)

Effect of l-theanine on glutamatergic function in patients with schizophrenia (2015)

A focus on memantine

Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia – an opportunity to target NO?


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